Meta-n-alkylamino para alkoxy phenyl arsonic acid and method of making the same



Patented Aug. 3, 1937 UNITED STATES PATENT OFFICE META N ALKYLAMINO PARA ALKOXY PHENYL ARSONIO ACID AND LIETHOD' OF MAKING THE SAME No Drawing. Application January 30, 1933, Serial No. 654,240

10 Claims.

Our invention relates to a new group of compounds which are especially useful as therapeutic agents, more particularly in the treatment of trypanosomiasis and syphilis, and method of preparing the same.

We have observed that the 3-amin0 derivative of para-hydroXy-phenyl-arsonic acid generally does not form substitutions in the amino group. The production of such substitution products is desirable in chemotherapy for the preparation of valuable medicinal compounds.

We have found, however, that such substitution in the amino group is possible when the hydroxyl group in the para position tothe arsonic acid group has been substituted to form oxy-derivatives.

According to our invention, we convert parahydroXy-phenyl-arsonic acid to para-alkyloxyphenyl arsonic acid, then introduce the N02 group in the 3-position, reduce the N02 to NH2,

and substitute on the NHz group.

Graphically, the procedure may be represented:

propiomc anhydride, and the like. Many of these pentavalent arsenicals of the newly described type can be further reduced sothat the arsonic acid group can be changed into the arseno group, which is well-known for its high trypanocidal and spirillicidal effects. Such arseno compounds are valuable in the treatment of trypanosomiasis and syphilis.

The final products contemplated by the present invention would thus have the following general formulas:

in which X is an alkyl radical such as methyl, forming a methoxy group; ethyl, forming an o 1|KS "(OH)2 1|KS/=(OH)2 1 is =(0H)2 i|XS=(OH)g A]is =(OH) N02 NHz NHY on OX OX OX OX The substituents X and Y are fully described ethoxy group; and higher homologues and below. isomers thereof; X may also represent a substi- We have d v p a methoil and produced a tuted alkyl radical containing oxygen, nitrogen,

large number of compounds which represent subetc, Such as arbomethyl forming Garbostitutions in the hydroxyl with the production of methoxy group, carboethyl forming a carbo methoxy derivatives and higher homologues of ethoxy group, or acetamide and its derivatives, 4 this genes such as fi i a g f qg such as acetyl anilide, and higher homologues 2 carbmmethoxy an Qgous enva Ives and isomers. Z represents substituents indior the same products. By nitration of the above- Gated below H mentioned compounds and subsequent reduction, We can produce the 3-nitro and S-amino deriva- 3 g .denvatlvff's have the fOHOWmg tives of this series of compounds, with the result em orm that a large number of new compounds are 0 formed. We have also prepared 2-nitro, Z-amino and substituted Z-amino derivatives of substi- 1llsOH- tuted para-hydroXy-phenyl-arsonic acid. Final- OH ly, in conformity with our theory, the 3-amino derivatives of substituted hydroxy-phenyl arsom'c acid give substitution products in the amino I N02 group, due to the interaction of acyl substances,

e. g., chlor-acetyl compounds such as chloracetic I acid and substitution products thereof, such as chloracetamide, .as well as acetic anhydride,

in which is the same as. in Formula (1).

The amino derivatives have the following general formula:

in which X is the same as in Formula (1).

The substituted amino compounds have the following general formula:

/0 AS OH OH NHY ' in which X is the same as in Formula (1) and Y is an acyl or a glycyl group, such as (a) an acetyl radical, CH3-CO, forming a substituted hydroxy-acetamino-phenyl-arsonic acid,

or a homologue thereof such as propionyl, butyryl, etc., R. representing the arsonic acid nucleus; (b) a carbomethyl radical CI-I2COOH forming a substituted hydroxy-phenyl glycine-arsenic acid, R(OX)NH.CI-Iz.-COOH; (c) CH2CONH2, forming a substituted hydroxyphenyl-glycine-amide-arsonic acid.

R( OX) NH-CH2CONH2;

(d) -CH2-CONHC6H5, forming a substituted hydroxy phenyl glycine anilide-arsonic acid, R(OX) NHCHzCONH-CsI-I5; (e)

forming a substituted hydroxy-phenyl-glycinetoluidide-arsonic acid,

or (f) -CH2CONHC6H4OH, forming a substituted hydroxy-phenyl-glycine-hydroxy-anilidearsonic acid,

R(OX) NHCH2CO-NHC6H4OH, and their various isomers. Hence, the substituent Y represents the group -CHz-CONH-X, where X represents hydrogen, phenyl, or a sub- 0 stituted phenyl, or an acyl group of general formula -OCCH2R, where R is hydrogen, methyl, or higher alkyl group.

The following examples are illustrative of our invention:

EXAMPLE I fied by recrystallization from water or by dissolving in alkali and reprecipitating with hydrocorresponding to the general Formula (1) given above.

The reaction may be represented:

From the above, the preparation of the analogous compounds referred to under Formula (1) above will be obvious.

EXAMPLE II 3-nitro-alkylwry-phenyLarsonic acids The following example of nitration will obviously apply, generally, to the other products referred to above.

13.7 grams of para-n-butyl-oxy-phenyl-arsonic acid, which may be prepared according to method described in Example I are dissolved in 40 cc. of sulphuric acid and cooled to 0-5 C. and nitrated with a mixture of 4.5 grams of nitric acid and 3 cc. of sulphuric acid allowing the temperature to rise to 15 C. This mixture is added to four volumes of crushed ice with stirring and the precipitated nitro compound is filtered ofi.

It may be recrystallized from water. The product is 3-nitro-4-n-butyl-oxy-phenyl-arsonic acid, and may be represented by the formula:

corresponding to general Formula (2) given above. 0

The reaction may be represented:

EXAMPLE III 3-amino-alkyl-oxy-phenyl-arsenic acids The following is a typical example of reduction to produce the 3-amino compounds:

24 grams of 3-nitro-4-ethoxy-phenyl-arsonic acid, which may be prepared according to method described in Example II, are dissolved in a solution of 20 grams of sodium carbonate in 160 cc. of water. This is added to a suitable reducing agent, preferably an alkaline paste of ferrous hydroxide, which is made as follows:

160 grams of ferrous sulphate are dissolved in 160 cc. of water and to this is added with stirring a solution of grams of sodium hydroxide. The material is cooled to 30 C. before adding to it the solution of the nitro compound.

Other reducing agents, such as sodium hydrosulphite, 'may be used.

After the nitro compound has been added to the reducing agent it is stirred for one hour and EXAMPLE IV Formula (3) given 3-acetyl-almino-a -ethomy-phenyl arsonic acid 36 grams of 3-nitro-4-ethoXy-phenyl arsonic acid, which may be prepared according to method described in Example II are dissolved in a solution of grams of sodium carbonate in 240 cc.

30 of water; This is added to suitable reducing agent such as an alkaline paste of ferrous hydroxide, which is made. by dissolving 240 grams of ferrous sulphate in 240 cc. of Water and to this is added with stirring a solution of 180 grams of sodium hydroxide. The material is cooled to 30 before adding to it the solution of the nitro compound. After the nitro compound is added it is stirred for one hour and filtered. Hydrochloric acid is added until neutral to litmus, and then add 25 cc. of acetic anhydride, and stir Well. A precipitate separates. Filter this and recrystallize from water. It crystallizes in fine needles. The product is 3-acetyl-amino-4-ethoxy phenyl arsonic acid and may be represented by the following formula:

o i xsoE OH -NHO 0-0113 OOzHs In the above manner the higher homologs of the acetyl group can also be introduced such as propionyl, butyryl, etc. Derivatives of propyloxy-, buty1-oxy-, etc. -arsonic acids can also be prepared by similar procedure.

EXAMPLE V 4-z'soamylory-1-arsom'c acid-phenyl-3-glycine anilz'de' 30 grams of 3-amino-4-iso-amyl-oxy-phenyl arsonic acid, which may be prepared according to the method described in Example III are dissolved in a solution of 4 grams. of sodium hydroxide in 100 cc. of Water.

After adding 17 grams of chloracetanilide' the mixture is refluxed for four hours, filtered and acidified with hydrochloric acid.

The 4-isoamyloxy-1-arsonic acid-phenyl-3- glycine-anilide is precipitated. It may be purified by dissolving it in dilute ammonium hydroxide,

treating with charcoal, filtering and repreci'pitating with dilute hydrochloric acid. It may be represented by the formula:

O CliHll corresponding to general Formula (4) given above.

The reaction may be represented:

3-amino-4carbomethoxy-phenyl arsonic acid cannot be isolated by reduction of the corresponding nitrc derivative because a molecule of water is eliminated with the formation of 3-hydroxy-1- 4-benzisoxazine-6-arsonic acid which does not react with chloracetyl compounds to form a substituted amino derivative.

However, if the alkaline solution from the reduction of the 3-nitro-4-carbomethoxy-phenylarsonic acid with the reducing agent, as described in Example III, is not acidified, the 3-amino-4- carbomethoXy-phenyl-arsonic acid remains as such in solution .and can then be condensed with an acyl compound, such as R OICHQCON where R is hydrogen or a phenyl group, to form glycine derivatives, such as 2-carbomethoxy-5-1 arsonic acid and phenyl-glycine-amide, or other glycine derivatives.

EXAMPLE VI N (z-carboxy-methomy-5-arsonic acid-phenyl) glycine-amide 51.2 grams of 3-nitro-4-carboXymethoxy-phenyl arsonic acid are dissolved in a solution of 40 grams of sodium carbonate in 320 cc. of water. This is added gradually With stirring to a ferrous hydroxide paste made by mixing together 320 grams of ferrous sulphate in 320 cc. of water and 240 grams of sodium hydroxide in 320 cc. of water.

After stirring for one hour the mixture is filtered, the clear filtrate is acidified until it is just neutral to litmus, and 6.4 grams of sodium hydroxide quickly added.

To this are added 30 grams of chloracetamide and refluxed for three hours. The mixture is cooled and acidified to congo with hydrochloric acid, precipitating the 4-carboXy-methoxy-l-arsonic acid-phenyl3-glycine-amide. This compound may be purified by dissolving it in dilute ammonium hydroxide, treating with some charcoal, filtering and precipitating with dilute hydrochloric acid. It may be represented by the general Formula (4) given above, and specifically:

While the substituted amino derivatives of carbo-methoxy-pheny1arsonic acid must be pre- 'pared by this method. for reasons explained above,

we prefer to use this method also for the preparation of substituted amino derivatives of other members of this series because it eliminates the isolation of the intermediate amino compound.

EXAMPLE VII Derivatives of 1-arsonio acid-phenyl-4-ory acetyl-anilide A compound of the type described in general Formula (1) which contains nitrogen in the substituted alkyl radical would be derivatives of 1-' arsonic acid-phenyli oxy acetyl-anilide, having the structuralformula:

'( )CH:CONHCeH5 This compound is known and has been previously prepared. However, the nitro and amino or substituted amino derivatives of this compound have not been previously described.

' The nitro compound is prepared as follows:

14.04 grams of l-arsonic acid-phenyl-i-oxy acetyl-anilide were dissolved in 42 cc. of sulphuric acid and cooled to 0 C. and nitrated with a mixture of 3.6 grams of nitric acid and 2.5 cc. of sulphuric acid, allowing the temperature to rise to 15 C. This mixture was added to four volumes of crushed ice with stirring and filtered ofi. It is purified by solution in dilute ammonium hydroxide, treatment with a small quantity of decolorizing carbon such as nuchar and reprecipitation with hydrochloric acid. The product is'3-nitro-l-arsonic acid 4-phenoxy acetyl anilide and may be represented by the formula:

0 CHzC O-NH-CtHB The amino compound is formed by reduction of the above nitro compound as follows:

16 grams of 3-nitro-1-arsonic acid 4-phenoxy acetyl-anilide are dissolved in a solution of 10 grams Nat-2C0; in cc. of H20. This is added to an alkaline ferrous hydroxide paste which is made as follows: 80 grams of ferrous sulphate are dis solved in 80cc. H20 and to this is added with stirring a solution of 60 grams NaOI-I in 80 cc. H2O. This is cooled to 20 C. before adding to it the solution of the nitro compound.

This addition is made with stirring and allowing the mixture to reactfor one hour. It is then filtered, the precipitate washed thoroughly and the combined filtrates neutralized to Congo red with hydrochloric acid. The amino compound is filtered off and purified by solution in dilute ammonium hydroxide and reprecipitation with hydrochloric acid. The compound is3-amino-1- arsonio acid phenyl-4-oxy acetyl anilide and has this formula:

0 As0 H The acetyl derivative of this compound having the formula:

MP0 o-o1i= ronic O-NHCH5 has been prepared by us.

The pentavalent arsenicals produced according to above-mentioned reactions may be further.

reduced so that the arsonic acid group is changedto an. arseno g p.

EXAMPLE VIII 4 ,4-carboxymeth0:cy-3,3'-N-(glycine-parahydro ry-anilide) arseno-benzene- Four grams of -N(2-carboxymethoxy-5-arsonic acid-phenyl) glycine-para-hydroxy-anilide are dissolved in 20 cc. of water with the aid of two molecules of sodium hydroxide. This solution is cooled and added slowly to a cooled solution'of four grams of magnesium chloride and twentyfive grams of sodium hydrosulphite in cc. of.

Water.

The mixture is filtered and warmed with continuous stirring for one hour at 55 C. The arseno compound separates as a light yellow precipitate which is 4,4-carbomethoxy-3,3-glycinepara-hydroxy-anilide-arseno-benzene and may be represented by the formula:

OCHzCOOH OOH2COQH In the same manner we have reduced to corresponding arseno derivatives the followingarsonic acid compounds:

as well as other arsonic acid derivatives mentioned in this specification.

Salts All of the compounds described above react with alkali metal and alkaline earth bases to give salts.

It will be understood that we have given above only certain preferred embodiments of our invention as examples, and that various other embodiments, as well as modifications, variations, and improvements. coming Within the spirit of our invention will probably suggest themselves to those skilled in the art. Hence, we do not wish to be restricted to the above examples or uses mentioned, except to the extent indicated in the appended claims, Which are to be interpreted as broadly as the state of the art Will permit.

We claim as our invention:

1. A compound having the following formulawherein X is an alkyl group higher than methyl and Y is an acyl group.

2. A method of forming an amino substitution derivative of 3-amino-para-hydroxy-phenyl-arsonic acid, comprising substituting an alkyl residue in the hydroxy group of para-hydroXy-phenyl-arsonic acid to form a para-alkyloxy-phenylarsonic acid, nitrating the latter to form a 3- nitro-para-alkyl-oxy-phenyl arsonic acid, reducing the latter to form a 3-amino-alky1oxy-phenyl arsonic acid, and reacting upon the latter compound with a compound containing an acyl group to produce a compound having the formula l xsowH where R is hydrogen or a phenyl group.

4. A method comprising substituting an alkyl group in the hydroxyl group of para-hydroxyphenyl-arsonic acid, nitrating to form a 3-nitropara-alkyloxy-phenyl-arsonic acid, reducing the latter, and treating the 3-amino compound thus obtained to produce a compound having the formula A50 (OH):

NHY

wherein X is an alkyl radical, and Y is an acyl group.

5. A compound having the following formula- NHY NHY

wherein X is an alkyl radical, and Y is a member of the class consisting of the acetyl group and homologs thereof.

7. A phenyl arsonic acid prepared according to the process described in claim 2.

8. A phenyl arsonic acid prepared according to the process described in claim 3.

9. A phenyl arsonic acid prepared according to the process described in claim 4.

10. A phenyl arsonic acid prepared according to the process described in claim 6.

GEORGE W. RAIZISS. LE ROY W. CLEMENCE. ABRAHAM I. KREMENS. 

